Peroxisome proliferator-activated receptor signaling

Thiazolidinediones are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-y). Stimulation of PPAR-y results in a number of intracellular and extracellular changes, including an increased number of insulin receptors, increased insulin receptor sensitivity, decreased plasma fatty acid levels, and an increase in a host of intracellular signaling proteins that enhance glucose uptake. 

Miyata, K.S., McCaw, S.E., Patel, H.V., Rachubinski, R.A. Capone, J.P. (1996) The orphan nuclear hormone receptor LXR a interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. J. biol. Chem., 271, 9189-9192... 

Baker PRS, Lin Y, Schopfer FJ, Woodcock SR, Groeger AL, Batthyany C, Swooney S, Long MH, lies KE, Baker LMS, Branchaud BP, Chen Y, Freeman BA. Fatty acid transduction of nitric oxide signaling Multiple nitrated unsaturated fatty acid derivatives exist in human blood and urine and serve as endogenous peroxisome proliferator-activated receptor ligands. J. Biol. Chem. 2005 280 42464-42475. 

Yoshikawa T, Ide T, Shimano H, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Yatoh S, Kitamine T, Okazaki H, Tamura Y, et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-Ic promoter through inhibition of LXR signaling. Mol. Endocrinol. 2003 17 1240-1254. 

Desvergne, B., A, 1. J., Devchand, P. R., and Wahli, W. (1998). The peroxisome proliferator-activated receptors at the cross-road of diet and hormonal signalling. J Steroid Biochem Mol Biol 65,... 

Burgermeister, E., Schnoebelen, A., Flament, A. et al. (2006) A novel partial agonist of peroxisome proliferator-activated receptor-y (PPARy) recruits PPARy-coactivator-la, prevents triglyceride accumulation, and potentiates insulin signaling in vitro. Molecular Endocrinology, 20, 809-830. 

Lemberger, T., Desvergne, B., and Wahli, W. (1996) Peroxisome proliferator-activated receptors a nuclear receptor signaling pathway in lipid physiology. Annu. Rev. Cell Dev. Biol. 12, 335-363. 

SREBPs interact with several co-activators and act in conjunction with several other transcription factors (Bengoechea-Alonso and Ericsson, 2007 Weber et ah, 2004). This could lead to other signal-sensitive co-activation of SREBP activity. For instance, the peroxisome proliferator activated receptor general co-activator (3 (PGC-1 p) interacts with and stimulates SREBP-lc activity in the liver of mice fed a diet rich in saturated fatty acids (Lin et ah, 2005). Chromatin remodelling complexes have also recently been shown to interact with SREBP-lc and contribute to insulin sensitivity (Lee et ah, 2007). 

Woifrum, C., Borrmann, C. M., Borchers, T., and Spener, F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein a signaling path to the nucleus. Proc Natl Acad Sci U S A 98 (2001) 2323-2328. 

Shi, Y., M. Hon, and R.M. Evans (2002). The peroxisome proliferator-activated receptor delta, an integrator of transcriptional repression and nuclear receptor signaling. Proc. Natl. Acad. Sci. USA 99, 2613-2618. 

More than 70% of differentiated thyroid cancer concentrates radioiodine after TSH stimulation (Robbins et al., 1991 Jarzab et al., 2003). Some differentiated thyroid cancer (approximately 10-20%), as well as anaplastic thyroid cancer, however, do not concentrate radioiodide, even after TSH stimulation (Robbins et al., 1991). Since almost all differentiated thyroid cancer expresses TSHR (Brabant et al, 1991), the absence of NIS induction in response to TSH is most likely due to defects in postreceptor signaling pathways. Recent studies have demonstrated the potential for NIS induction in poorly differentiated thyroid cancer by redifferentiation agents, such as nuclear receptor ligands, RA and peroxisome proliferator-activated receptor- (PPAR ) ligands, and inhibitors of epigenetic modifications. 

Khan, AH and Pessin, JE, Insulin regulation of glucose uptake a complex interplay of intracellular signalling pathways, Diabetologia, 2002. 45(11) 1475-1483. Kliewer, SA, Lenhard, JM, Willson, TM, Patel, I, Morris, DC, and Lehmann, JM, A prostaglandin j2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell, 1995. 83(5) 813-819. 

Moreover, studies about lipidogenesis and lipid metabolism have focused on a nuclear receptor, peroxisome proliferation-activated receptor y (PPAR-y). PPAR-y gene is a good example for involvement in a gene-environment interaction. Activation of PPAR-y leads to peroxisome proliferation and increased oxidation of fatty acids. PPAR-y activation results in adipocyte differentiation as well as improved insulin signaling of mature adipocytes. PPAR-y is associated with insulin resistance and blood pressure [5]. In individuals with a specific polymorphism in the PPAR-y (Prol2Ala), a low polyunsaturated-to-saturated fat ratio has been demonstrated to be associated with an increase in body mass index and fasting insulin concentrations [88]. 

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